polymeric nanoparticles for breast cancer therapy: a ... · nanoparticles' advancements for...

https://biointerfaceresearch.com/ 11151

Review

Volume 11, Issue 4, 2021, 11151 - 11171

https://doi.org/10.33263/BRIAC114.1115111171

Polymeric Nanoparticles for Breast Cancer Therapy: A

Comprehensive Review

Ikmeet Kaur Grewal 1,2 , Sukhbir Singh 1,* , Sandeep Arora 1 , Neelam Sharma 1

1 Chitkara College of Pharmacy, Chitkara University, Punjab, India 2 Department of Pharmacy, Government Medical College, Patiala, Punjab, India

* Correspondence: [email protected];

Scopus Author ID 56402098100

Received: 5.11.2020; Revised: 3.12.2020; Accepted: 5.12.2020; Published: 9.12.2020

Abstract: Breast cancer is a leading death cause in women globally. Since therapeutic products do not

yet approach the tumor tissue at adequate levels; therefore, nanoparticle-based chemotherapy has been

explored nowadays. Implementing nanotechnology to the treatment of breast cancer renders

chemotherapy very successful and efficacious but far less toxic. In this review article, literature about

polymeric nanoparticles applications in breast cancer was retrieved from PubMed, ScienceDirect, and

Google Scholar databases. This review paper briefly addresses molecular targets in breast cancer's

pathophysiology, drawbacks of current therapies for breast cancer, and polymeric nanoparticles as an

evolving breast cancer chemotherapy that includes benefits, critical characteristics, and passive and

active tumor targeting via polymeric nanoparticles. An outline of progression in polymeric

nanoparticles for breast cancer treatment reports in current publications; patents available and clinical

trials conducted for breast cancer in the last few years have been reviewed briefly.

Keywords: breast cancer; chemotherapy; clinical trials; patents; polymeric nanoparticle; tumour

targeting.

© 2020 by the authors. This article is an open-access article distributed under the terms and conditions of the Creative

Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

1. Introduction

Breast cancer is the most frequent carcinoma in females and a common cause of cancer-

related mortality in women worldwide [1,2]. Chemotherapeutic agents, combined with

radiation therapy and surgical intervention, constitute the first treatment option for breast

cancer [3]. However, pharmacotherapy has been modified since medicinal products do not yet

penetrate the tumor site at adequate levels, increasing systemic side effects, and reduced

pharmacokinetics. The application of nanotechnology for breast cancer treatment makes

chemotherapy more efficient and successful, and less harmful. Several types of cancers acquire

multidrug resistance, which seems to be a critical reason for several chemotherapeutics

categories' failure.

Consequently, over the past couple of years, different hybrid polymer nanoparticles

have been designed to treat breast cancer. In recent years, nanoparticles have been designed for

in-vivo cancer diagnostics, molecular biology screening of biological markers for tumors, and

targeted medications delivery. Such nanotechnology-based strategies could be primarily used

to treat various malignant conditions [4].

The literature was retrieved from databases like PubMed, Google Scholar, and

ScienceDirect for this article's compilation. Patents regarding nanoparticles in the treatment of

breast cancer have been collected from the WIPO. Clinical trials based related to breast cancer

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https://creativecommons.org/licenses/by/4.0/

https://orcid.org/0000-0002-4779-160X

https://orcid.org/0000-0003-0692-7002

https://orcid.org/0000-0001-5718-8698

https://orcid.org/0000-0002-5200-7330



have also been summarized in this review. The key terms utilized were ‘breast cancer’,

‘polymeric nanoparticles’, and ‘formulation for breast cancer’ in different combinations. This

review article briefly discusses molecular targets in breast cancer pathophysiology, limitations

of current breast cancer treatments, and polymeric nanoparticles as a promising technology

designed for breast tumor treatment, which includes advantages, essential characteristics, and

active and passive tumor targeting polymeric nanoparticles. An overview of polymeric

nanoparticles' advancements for breast cancer therapy reported in recent publications, patents

published, and clinical trials conducted related to breast cancer therapy in the last few years

has been summarized.

2. Molecular Targets, Types, and Detection of Breast Cancer

The main molecular targets identified to be involved in the pathophysiology of breast

cancer include estrogen receptor alpha (ERα) and epidermal growth factor-2 (ERBB-2). ERα

is a steroid hormone receptor expressed in about 70% of cases of invasive breast cancers. It is

a transcription factor which on activation through estrogen, stimulates oncogenic development

pathways within breast cancer cells [5-11]. ERBB-2 is over-expressed in around 20% of breast

cancers. Besides these, triple-negative breast cancer (TNBC) accounts for approximately 15%

of all breast tumors. It has been characterized by a lack of activation of molecular targets such

as estrogen and progesterone receptors or ERBB2 receptors. The different types of breast

cancer and TNBC have been depicted in Figure 1 [12-19].

Figure 1. Types of breast cancer.

Basal-like-1 TNBC is characterized by a high response to DNA damage as well as Ki67

levels. The androgen receptor is abundantly expressed in the luminal androgen receptor, with

an abundance 10-times stronger than the other subtypes. The mesenchymal stem-like TNBC is

distinguished by elements that interact with G-protein receptors, calcium signaling, and EGFR.

The immunomodulatory TNBC is attributed to the greater expression of STAT genes that

control T and B-cells and natural killer cells. The techniques for breast cancer detection have

been depicted in Figure 2 [20-30].

Types of breast cancer

According to site

Non-Invasive

Invasive

Frequently occurring (carcinoma in situ)

Lobular

Ductal

Less commonly occurring

Medullary

Mutinous

Tubular

Infiltrating carcinoma

Lobular

Ductal

Inflammatory breast cancer

Paget's disease

Phylloides tumour

Triple-negative breast cancer (subtypes)

Basal-like 1 and 2

Luminal androgen receptor

Mesenchymal and mesenchymal stem-like

Immunomodulatory





Figure 2. Technique for the detection of breast cancer.

3. Limitations of Current Breast Cancer Treatments

Existing treatment strategies have several shortcomings in the treatment of breast

cancer, which includes lack of selective toxicity, which leads to diminished therapeutic efficacy

and, as an outcome, the medical diagnosis being impaired; injury to healthy tissues and

therefore, decreased doses of anticancer medicines are generally delivered to minimize toxicity

to normal tissues; poor bio-distribution and drug penetration in solid tumors; heterogenic

vessels in tumor sites increases extravasation of drugs. Current treatments tend greater drug

deposition in normal viscera (10- to 20-fold greater) than that in a comparably loaded tumor

site, and several chemotherapeutic agents are unable to permeate from the vasculature more

than 40-50 mm (equivalent to the combined diameter of three to five cells) which could result

in multiple drug resistance (MDR) and ultimately therapeutic failure. Furthermore, the

development of MDR in tumor cells on treatment with one anticancer molecule could generate

resistance to an entire range of drugs owing to over-expression of drug efflux proteins [31-34].

4. Polymeric Nanoparticle as an Emerging Technology for Breast Cancer Therapy

4.1. Advantages of polymeric nanoparticles.

Nanotechnology offers a more targeted stratagem for resolving conventional

chemotherapies' shortcomings and may have great advantages for people living with cancer.

Polymeric nanoparticles include several benefits against free drugs, such as drug safety against

initial deterioration, increased drug permeability into a targeted tissue, controlled delivery of

drug and augmented intracellular permeation, drug avoidance from preterm physiological

interference, and diminished toxicity [35, 36].

4.2. Essential characteristics of polymeric biomaterials.

Biocompatible polymers must be employed to manufacture polymeric nanoparticles to

acquire quick and effective clinical translation. Furthermore, these nanocarriers should be

Types of breast cancer

Breast Self-Examinations

Clinical Breast Examinations

Mammography

Full-Field Digital Mammography

Computer-Aided Detection

Modalities Using Ultrasound

B-Mode Ultrasound

Compound Imaging

Doppler Ultrasonography

Magnetic Resonance Imaging

Nuclear Medicine

Radioimmunoscintigraphy

99m-Tc-Sestamibi Scintimammography

Positron Emission Tomography





surface functionalized to achieve extended biological circulation, least tendency to

aggregation, and superior uptake efficiency in targeted tumor cells. The examples of polymers

that could be utilized for the manufacturing of polymeric nanoparticles include poly-lactic-co-

glycolic acid (PLGA), poly-lactic acid (PLA), polyethylene glycol (PEG), chitosan, alginate,

and pectin [35, 36].

4.3. Active tumor targeting.

Targeting agents that could be conjugated over the surface of nanocarriers includes

proteins, i.e., antibodies, peptides, aptamers, nucleic acids, small organic molecules, vitamins,

and carbohydrates. The particular marker should be over-expressed on cancerous cells in

comparison to healthy tissues, and targeting nanocarriers should have great selectivity to

molecules that are distinctively expressed over the tumor cell’s surface. When specific entities

are being used to transmit nanocarriers to solid tumors, it’s indeed vitally important that agents

links to receptors specifically expressed on the target cells [37-42].

4.4. Passive targeting.

Passive targeting of circulating nanoparticles into tumor cells could be achieved

through enhanced permeation and retention effect (EPR), which has been schematically

represented in Figure 3 [37-42].

Figure 3. Passive tumor targeting via enhanced permeation and retention effect.

5. Recent Advancements in Nanotechnology-Based Formulation for Breast Cancer

Therapeutics

Innovative nanotechnology approaches have become essential for dealing with

challenging illness conditions. Consequently, the relevance of promising polymeric

nanoparticles strategies like stealth, magnetic, conjugated, and hybrid nanoparticles for breast

cancer therapy has become necessary currently. Table 1 summarizes the recent applications of

polymeric nanoparticles for breast cancer chemotherapeutics. Table 2 recapitulates the current

patents based on the relevance of nanoparticles in breast tumor management.

Table 1. Recent polymeric nanoparticles explored for breast cancer therapeutics. Drug Polymer/lipid Preparation

technique

Outcomes Refs.

Doxorubicin

Poloxamer 407, holo-transferrin Modified thin-film

hydration

Overcome drug-resistant

chemotherapy

[43]





Drug Polymer/lipid Preparation

technique

Outcomes Refs.

Doxorubicin HPMA,

GFLGKGLFG (peptide)

RAFT

polymerization

Potential drug delivery vehicle for

breast cancer

[44]

Erlotinib and

Doxorubicin

N,N-Diisopropylethylamine, N-

hydroxysuccinimide

Nano-precipitation Enhanced therapeutic effects and

sequential drug delivery

[45]

Tamoxifen Pluronic F-68, Pluronic F-108, Poly-

(ethylene oxide)-modified

polycaprolactone

Solvent

displacement

Preferential tumor-targeting and

circulating drug reservoir

[46]

Paclitaxel Polyethoxylated castor oil (Cremophor) - Treatment of patients with advanced

breast cancer

[47]

Docetaxel Triethylamine, PLGA, antibody-

conjugated magnetic nanoparticles

Solvent evaporation Showed sustained release; great

affinity and ultra-sensitivity to cancer

cell

[48]

Rapamycin,

Piperine

PLGA Nano-precipitation Superior treatment of breast cancer via

co-delivery

[49]

Rapamycin PLGA Single emulsion

solvent evaporation

Drug targeted to epidermal growth

factor receptor; efficient tumor

selectivity

[50]

Danamycin PLGA, N,N-dicyclohexyl-carbodiimide,

triethylamine

Nano-precipitation Folate receptor targeted [51]

Curcumin

Bovine serum albumin Desolvation Treatment of breast cancer

[52]

Doxorubicin

hydrochloride

PLGA 50:50 Double emulsion

diffusion

evaporation

Reduced cardio-toxicity [53]

Salinomycin,

Paclitaxel

PLGA Emulsion solvent

diffusion

Overcome cancer recurrence due to

resistant cell population

[54]

AXT050

(collagen-IV

derived bio-

mimetic

peptide)

PLGA-PEG nanoparticle Emulsion method Enhanced anticancer activity [55]

Calcitriol

PLA Nano-precipitation Sustained and prolonged anticancer

activity; Improved therapeutic

efficiency

[56]

Paclitaxel PLGA 50:50 Emulsion solvent

diffusion

evaporation

Efficacy enhancement in

chemotherapy

[57]

Docetaxel PLGA, PEG, super-paramagnetic iron

oxide

Modified emulsion

evaporation

Outstanding drug delivery strategy for

breast cancer

[58]

Doxorubicin Poly-(methacrylic acid), Polysorbate 80-

grafted-Starch

Targeting brain metastases of breast

cancer

[59]

Tamoxifen

citrate

PLGA Multiple emulsion

solvent evaporation

Enhanced permeation into breast

cancer cells

[60]

Paclitaxel-

thymo-quinone

Single emulsion

solvent evaporation

Dual drug therapy displayed superior

anticancer activity and could alleviate

the toxic effects of paclitaxel through

dose reduction

[61]

Curcumin;

doxorubicin

(pH-sensitive)

PLGA, Polyethylene glycol, L-glutamic

acid

Nano-precipitation Potentially useful for refractory breast

cancer

[62]

Taxols,

Trastuzumab,

Paclitaxel

PLGA, montmorillonite

(Multi-functional nanoparticle)

Modified solvent

extraction/

evaporation

Provides effective breast cancer

therapy

[63]

Methotrexate,

Curcumin

PLGA, Resomer Treatment or control of cancer

progression

[64]

Docetaxel Poly-(L-g-glutamyl glutamine) Nano-precipitation Targeted, localized, and effective

delivery in the tumor site

[65]

Docetaxel

Poly (ε-caprolactone),

Pluronic F68

Modified solvent

displacement

Potential therapy of breast cancer [66]

Paclitaxel 5-methyl-2-(2,4,6-trimethoxyphenyl)-

[1,3]-5-dioxanylmethyl methacrylate),

(1,4-O-methacryloylhydroquinone)

Miniemulsion

polymerization

Treatment of breast cancer [67]

Rapamycin Hyaluronic acid, CD44-tropic (ligand), 3-

amino-4-methoxy-benzoic acid

Chemical reaction

and conjugation

Localized, sustained, and controlled

drug delivery to CD44-positive breast

cancer cells

[68]

Paclitaxel

PLGA Modified nano-

precipitation

Breast cancer treatment [69]

Docetaxel Mannitol, poly-(D,L-lactide-co-glycolide)-

D-α-tocopheryl polyethylene glycol 1000

succinate

Modified nano-

precipitation

Breast cancer treatment [70]

Paclitaxel,

lapatinib

Pluronic F127 Thin-film hydration Better therapy in drug resistant

metastatic breast cancer

[71]

Paclitaxel Polyvinylpyrrolidone, polyethyleneimine,

poly(methyl vinyl ether-alt-maleic

Solvent evaporation Improved drug delivery to cancer cells [72]






technique

Outcomes Refs.

hydrochloride), poly(allylamine

hydrochloride), poloxamer 188

Doxorubicin

(Thiolated

chitosan)

(N-acetyl cysteine-chitosan), (N-acetyl

penicillamine-chitosan), ASOND

Gelation Efficient drug delivery system [73]

Baicalin

PLGA, Labrafil M2125 CS oil, Tween 80,

Poloxamer P407

Nano-precipitation Promising in potentiating anticancer

activity

[74]

Tamoxifen PLGA, poly(vinyl alcohol), polyvinyl-

pyrrolidone, HER2-antibody (conjugation)

Double emulsion-

solvent evaporation

(multi-functional

nanoparticle)

Improved efficiency; targeted and

sustained delivery

[75]

Doxorubicin Monophosphoryl lipid A, Thioketal cross-

linker

Conjugation (ROS

switchable nano-

platform)

Good tumor-targeting; reduced

systemic toxicity

[76]

Doxorubicin

Polyvinyl alcohol, PEG,

polyvinylpyrrolidone

Chemical reduction

(silver/polymeric

dual nanoparticle)

Enhanced cytotoxic effect by

combinatorial therapy

[77]

Vincristine

sulfate

PLGA, PEG, folic acid (conjugation) Emulsion solvent

evaporation

Enhanced cellular uptake and higher

cytotoxicity

[78]

Curcumin N-isopropylacrylamide, Methacrylic acid Polymerization Breast cancer treatment [79]

Simvastatin Cholic acid, PLGA Modified nano-

precipitation

Breast cancer chemotherapy [80]

Doxorubicin

Chitosan, Copper (II) Chloride,

doxorubicin

Single reduction (pH

sensitive coated

copper oxide

nanoparticle)

Showed pH-dependent drug release [81]

Curcumin

Bovine serum albumin, polyethylene

glycol

Desolvation Improved efficacy for breast cancer [82]

Cisplatin,

paclitaxel

Poly(2-oxazoline) Thin film Improved chemotherapy of ovarian

and breast cancer; potential for clinical

translation

[83]

Chrysin- PEG, PLGA Promising in breast cancer therapy [84]

Paclitaxel Alginate Nano-emulsification

polymer cross-

linking

Enhanced antitumor effects for breast

cancer

[85]

Docetaxel

Trastuzumab

Chitosan, D-α-tocopherol polyethylene

glycol 1000 succinate

Modified solvent

evaporation

Improved targeted drug delivery; less

toxicity

[86]

Letrozole Poly (D, L-Lactide) Emulsion-solvent

evaporation

Treatment of hormonally-positive

breast cancer in postmenopausal

women

[87]

Docetaxel Human serum albumin High-pressure

homogenization

Promising as immuno-nanoparticle

delivery for breast cancer

[88]

Paclitaxel PLGA, hyaluronic acid (surface

engineering)

o/w emulsion Decreased IC50 of paclitaxel on triple-

negative breast cancer cells

[89]

Methotrexate,

Beta-carotene

Nano-precipitation

(hybrid

nanoparticle)

Treatment of Breast cancer [90]

Doxorubicin

[Folic acid and

trastuzumab

conjugated]

PEG, (Redox responsive random multi-

block co-polymeric nanocarrier)

Nano-precipitation Targeted drug delivery in cancer

therapy

[91]

Anastrozole Polycaprolactone, PEG, stearic acid Direct

emulsification

solvent evaporation

(hybrid

nanoparticle)

Enhanced therapeutic activity [92]

Docetaxel H40 (dendritic polyester), poly-(D,L-

lactide)

Modified nano-

precipitation

Feasible for cancer treatment [93]

Docetaxel PLA, Labrafac CC Emulsion diffusion

(oily core polyester

nanocapsule)

Controlled drug delivery [94]

Simvastatin PLGA Nano spray drying

(polymeric

submicron particles)

Treatment of solid tumor [95]

Thiolated

nanoparticle

Gelatin, PEG Utilized to target drugs/genes to solid

tumors passively

[96]

Lapatinib

ditosylate

Tocopheryl polyethylene glycol-1000

succinate, PLGA

Polymerization Optimal therapeutic effect in breast

cancer treatment

[97]

Nutlin-3a PLGA Single oil-in-water

emulsion

Targeted drug delivery for breast

cancer therapy

[98]

Doxorubicin

17-AAG

PEG-b-PGA copolymer, polypeptide-

based nano-gel

Block ionomer

complex

Synergistic combination overcomes

drug’s solubility issues

[99]

Thymo-

quinone

PLGA, PEG, Pluronic F68 Solvent evaporation Showed selective cytotoxic result

toward UACC 732 compared to MCF-

7 breast cancer cells

[100]






technique

Outcomes Refs.

Doxorubicin,

GG918

(Elacridar)

Ultra-sonication Simultaneous delivery with the

superior treatment of multidrug-

resistant breast cancer

[101]

Vinorelbine PLGA, PEG, aptamer (bio-conjugate) Emulsion/solvent

evaporation

Targeted effect for breast cancer [102]

Paclitaxel,

(stealth

nanoparticle)

Poly-(ethylene glycol)-block-poly(ε-

caprolactone), soybean

phosphatidylcholine, cholesterol

Thin film hydration Improved drug accumulation at the

target tumor site achieved via PEG

modification

[103]

Docetaxel PLGA (polymer hybrid nanoparticle) Nano-precipitation Advanced therapeutics to combat

breast cancer

[104]

Doxorubicin PLGA, lecithin, DSPE-PEG-2000 (Lipid-

polymer hybrid nanoparticle)

Single-step modified

nano-precipitation

Controlled drug (both hydrophilic/

lipophilic form) delivery

[105]

Docetaxel Mono-methoxy-PEG-PLA Thin-film hydration Showed better antitumor efficacy in

breast cancer therapy

[106]

Curcumin- PLGA Solvent evaporation Improved bioavailability of curcumin

for the treatment of severe malignant

breast cancer

[107]

Curcumin Chitosan, folic acid - Potential drug delivery for breast

cancer therapy

[108]

Dasatinib Poly(cyclohexene phthalate)

Nano-precipitation Controlled drug delivery for breast

cancer treatment

[109]

17-AAG: 17-allylaminodemethoxygeldanamycin; ASOND: antisense oligonucleotide; IC50: drug concentration

which is required for 50% inhibition in-vitro; DSPE-PEG-2000: 1,2-distearoyl-sn-glycero-3-

phosphoethanolamine-N-[amino(polyethylene glycol)-2000]; HPMA: N-(2-Hydroxypropyl) methacrylamide);

PEG: polyethylene glycol; PLGA: Poly-(D,L-lactide-co-glycolide); PLA: Poly-(D,L-lactic acid), RAFT:

reversible addition-fragmentation chain-transfer; ROS: reactive oxygen species.

Table 2. Recent patents based on the relevance of nanoparticles in breast cancer therapy.

Patent name Patent number Applicant Year Refs.

Liposomal curcumin for the

treatment of cancer

WO/2004/080396 The University of Texas Md Anderson 2004 [110]

In vivo imaging and therapy with

magnetic nanoparticles conjugates

WO/2007/021621 Board of supervisors of Louisiana state

university and agricultural and

mechanical college

2007 [111]

In-vivo imaging and therapy with

magnetic nanoparticles conjugates

EP1912564 Univ Lousiana state 2008 [112]

Breast cancer therapy based on

hormone receptors status with

nanoparticles comprising a taxane

WO/2008/076373

CA2672618

EP2117520

US20100048499

Abraxis Bioscience, LLC 2008 [113]

[114]

[115]

[116]

In-vivo imaging and therapy with

magnetic nanoparticle conjugates

US20090169478 Board of supervisors of Louisiana state

university

2009 [117]

Hydrogel nanoparticles used as

injectable subcutaneous implant

agent

CN101953775 Zhengzhou University 20111 [118]

Target cellular delivery

nanoparticles

US20110077581 Georgia Tech Research Corporation 2011 [119]

Bioconjugation of calcium

phosphosilicate nanoparticles for

selective targeting of cells in vivo

WO/2011/057216 The Pennsylvania state research

foundation

2011 [120]

All field simultaneous radiation

therapy

US08173983 Sahadevan Velayudhan 2012 [121]

Specific detection method of human

breast cancer cells MCF-7 based on

surface-enhanced Raman

spectroscopy

CN102608102 Nanjing Normal University 2012 [122]

Development and use of polymer

nanoparticles comprising

poly[epiloncaprolactone and

doxorubicin

WO/2012/104461 Servicio Andaluz De Salud,

Universidad De Granada

2012 [123]

NTS-polyplex nanoparticles system

for gene therapy of cancer

WO/2012/107908 Centro De Investigación Y De

Estudios Avanzados Del Instituto

Politécnico Nacional

2012 [124]

Nano-gelatin encapsulated

composition of glutathione reductase

and lycopene

IN3233/CHE/2012 Mary Anne Preethe. K 2012 [125]

Tripterine nanostructure lipid carrier

modified by lentiviral vector and

appliance for preparing and treating

CN102670510 Jiangsu Provincial Academy of

Traditional Chinese Medicine

2012 [126]






prostatic cancer, lung cancer, and

breast cancer drug

Popcorn shape gold nanoparticles

for targeted diagnosis, photothermal

treatment, and in-situ monitoring

therapy response for cancer and

multiple drug resistance bacteria

US20120302940

Ray Paresh Chandra 2012 [127]

Immune-Stimulating photoactive

hybrid nanoparticles

WO/2013/012628 University of Georgia Research

Foundation, Inc.

2013 [128]

Breast cancer therapy based on

hormone receptor status with

nanoparticles comprising taxane

US20130280337 Abraxis BioScience, Lic. 2013 [129]

NTS-polyplex nanoparticles system

for gene therapy of cancer

CN103458931 Ct Investig Y Estudios Del Ipn 2013 [130]

Methods of treating breast cancer

using nanoparticles comprising

taxane-based on hormone receptor

status

JP2014080443 Abraxis BioScience, LLC 2014 [131]

Modular polymer hydrogel

nanoparticles and methods of their

manufacture

US20140220346 Memorial Sloan-Kettering Cancer

Center

Massachusetts Institute of Technology

2014 [132]

Immune-stimulating photoactive

hybrid nanoparticles

US20140220143 University of Georgia Research

Foundation, Inc.

2014 [133]

Methods for detecting single

mismatches in DNA hybridization

reaction using gold nanoparticles

KR1020140097679 Korea university research and business

foundation

2014 [134]

Targeting modified gold nanorod

targeted drug delivery compound

and application of the delivery

compound to antitumor

photothermal therapy

CN104368000 Second Military Medical University,

PLA

2015 [135]

Method used for detecting the

content of adenosine triphosadenine

in the breast cancer cell with the

colorimetric biosensor and

constructed based on gold

nanoparticles

CN105717103 Nanjing Medical University 2016 [136]

Aptamer-modified gold

nanoparticle-graphene composite

material and preparation method and

application thereof

CN105879027 Suzhou Institute of Nano-Tech and

Nano-Bionics, Chinese Academy of

Sciences

2016 [137]

Nanoparticle-assisted ultrasound for

breast cancer therapy

US20150328485 Academia Sinica 2016 [138]

Fabrication method and application

of cellulose membrane of a drug

loading breast cancer- targeting

magnetic nanoparticles

CN106310256 South china normal university 2017 [139]

A process of preparing efficient

herbal nanoparticles of solasodine

for breast cancer

IN781/KOL/2015. Sarthak Bhattacharya [140]

Methods and compositions for

assaying blood levels of legumain

US20170089909 Xiaohong Yu Fang Guo 2017 [141]


assaying blood levels of legumain

US20170089910 Xiaohong Yu Ningbo ziyuan medical

devices Inc.

2017 [142]

Preparation method and application

of photosensitive magnetic

nanoparticles system capable of

inhibiting the growth of breast

cancer cells

CN106668871 South China Normal University [143]

Combination therapy comprising

nanoparticles of a taxane and

albumin with abt-263 in methods for

treating cancer

US20170202782 Abraxis BioScience, LLC 2017 [144]

Hyaluronic acid-based nanoparticles

as biosensors for imaging-guided

surgery and drug delivery vehicles

and methods associated therewith

US20170202982 Wake Forest University 2017 [145]

An anticancer compound US201741022701 Sree Balaji Medical College &

Hospital, Biher- Bharath University

2017 [146]






Application of N-fullerene amino

acid derivative nanoparticles to the

preparation of medicine for treating

tumor under illumination condition

and medicine

CN107551272 Beijing Funakang Biotechnology Ltd 2017 [147]

Nanoparticles silica gel capable of

being used as an injectable

subcutaneous implant.

CN107595768 Chengdu Angduo Biotechnology Co.,

Ltd

2018 [148]

Test support method for supporting

the prediction of complete

pathological response (PCR) using

fluorescent nanoparticles

EP3321682 Konica Minolta Inc 2018 [149]

Electrochemical detection method

for stem cells

CN108088882. China Stem Cell Group Shanghai

Biotechnology Co., Ltd.

2018 [150]

Polypeptide for promoting apoptosis

of breast cancer cells by targeted

uptake of siRNA

CN108117585 Hefei Novel Gene Technology Service

Co., Ltd

2018 [151]

Multifunctional RNA nanoparticles

and methods for treating cancer and

therapeutic resistant cancer

WO/2018/106992 University of Cincinnati 2018 [152]

Therapeutic cationic peptides and

unimolecular nanoparticles for

efficient delivery thereof

US20180235897 Wisconsin Alumni Research

Foundation

2018 [153]

Hyaluronic acid-decorated

thymoquinone-loaded Pluronic®

P123-F127 mixed polymer

nanoparticles as targeted therapy

against triple-negative breast cancer

IN201831021395 Adhikary, Arghya 2018 [154]

Specific targeted breast cancer cell

mesoporous silicon nanometer drug

loading system and preparation

method thereof

CN108671236. Maanshan People’s Hospital 2018 [155]

Keratin based nanobiocomposite for

cancer cell targeting and imaging

IN201741017595 C.Vijayalakshmi, R.Srinivasan,

Venkatesan

2018 [156]

Preparing of polyethyleneimine

modified photosensitizer-carried

Prussia blue magnetic nanoparticles

CN108904803 Southwest University 2018 [157]

Silk fibroin-based nanodrug for

targeted combined chemotherapy of

breast cancer, and preparation

method thereof

CN108926567 Southwest University 2018 [158]

Gold nanoparticles and synthetic

method thereof.

CN109047791 Henan University 2018 [159]


assaying blood levels of Legumain.

20190011451 Ningbo Ziyuan Medical Devices Inc 2019 [160]

HER2-targeted phase-change PLGA

nanoparticles, application and

preparation method thereof

CN109172829 Chongqing Medical University 2019 [161]

Osteotropic nanoparticles for

prevention or treatment of bone

metastases

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Brinker; Yu-shen Lin; Hon Leong

2019 [162]

Hyaluronic acid appended PEG-

PLGA coated quarternized

mesoporous Silica nanoparticles for

delivery of Mirnas in TNBC

IN201931006560 Adhikary, Arghya 2019 [163]

Near-infrared responsive nano-

composite supramolecular hydrogel

and preparation method thereof.

CN109503862 Tianjin University 2019 [164]

Application of nanogold-based

composite supermolecular hydrogel

as a biomedical material

CN109504648 Tianjin University 2019 [165]

Method and system for synthesizing

“green” biocompatible organic-

inorganic hybrid electrospun

nanofibers for potential biomedical

applications

IN201741034940 Kanapathy Gopalakrishnan 2019 [166]

Development of engineered gold

nanoparticles for high contrast

imaging of tumor in x-ray

IN201741038811 Selvamani Vijayakumar 2019 [167]






photography and pharmacokinetic

studies in vivo

Improved pharmaceutical

compositions of docetaxel polymeric

nanoparticles and preparations

thereof

IN201711038532 Department of Pharmaceutical

Engineering &Technology

2019 [168]

Macrophages membrane coated

breast cancer targeted nanoparticles

and preparation method thereof

CN109953972 Fudan University 2019 [169]

ROS-sensitive tumor-targeted gene

delivery system and preparation

method thereof


Preparation method of quercetin

nanoparticles and application of

quercetin nanoparticles in preparing

a drug for resisting breast cancer

CN109999002 Fuzhou University 2019 [171]

Pullulan nanoparticles with co-

supported lovastatin and

doxorubicin and preparation method

thereof.

CN110201181 Hunan Normal University 2019 [172]

Preparation and application of

nanoparticle doped RNA hydrogel

for targeted triple-negative breast

cancer

CN110327464. Linyi University 2019 [173]

Novel RGD-chitosan

oligosaccharide silicon

oxide/BCSG1-siRNA nanoparticle

breast cancer targeted therapy

method

CN110339372 Henan Cancer Hospital 2019 [174]

Decreased adhesivity receptor-

targeted nanoparticles for Fn14-

positive tumors

US20190328677 University of Maryland, Baltimor 2019 [175]

Preparation and application of nano-

immunological preparation based on

porous calcium carbonate

CN110420335 Shandong Normal University 2019 [176]

Multifunctional RNA nanoparticles

and methods for treating cancer and

therapeutic resistant cancer

US20190351067 University of Cincinnati 2019 [177]

Fructose and RGD peptide co-

modified dual-targeting triple-

negative breast cancer lipid material

CN110522923 Sichuan University., assignee.

Fructose

2019 [178]

Green synthesis of gold

nanoparticles using fruit extracts-

bael fruit, eugenia jambolana, and

sours

IN201741038806. Selvamani Vijayakumar 2019 [179]

Lipid Nanoparticles Loaded with

Ceranib-2 as Anticancer Agent.

WO/2020/018049. Invokat Intellectual Property Services 2020 [180]

Gold nanoparticle-ligand conjugates

and methods of use

WO/2020/041267. University of Okalahoma 2020 [181]

Preparation and application of breast

cancer targeted liposome modified

by biotin and glucose

CN110840844 Sichuan University 2020 [182]

Preparation method of CPZ-coupled

MS2 protein nanoparticles and

application thereof in breast cancer

resistance

CN110841073 Fuzhou University 2020 [183]

Application of copper-palladium

alloy nanoparticles and autophagy

inhibitors in preparing tumor-killing

drugs or kits based on photothermal

effects

CN110893237 South China University of Technology 2020 [184]

Preparation and application of multi-

branch biotin modified breast cancer

targeted liposomes.

CN110917139 Sichuan University 2020 [185]

Calcium phosphate-lipid nano-drug

co-delivery system consisting of low

molecular weight heparin and

prodrug of natural drug







Adriamycin-indocyanine green

bionic nanoparticles and application

thereof

CN111000822 Shenyang Pharmaceutical University 2020 [187]

Use of mutant P53 gene-targeted

lead borate nanoparticles in cancer

treatment and production method of

these nanoparticles

WO/2020/086014 Yeditepe University 2020 [188]

Ph-Activated nanoparticles WO/2020/092602 Ohio State Innovation Foundation 2020 [189]

A formulation and evaluation of the

peptide Hif9 loaded chitosan

nanoparticles

IN202041013943 Manimaran, D.; N Elangovan.;

Jagatheeh, K

2020 [190]

Targeted nanoparticles for

glioblastoma theranostics

US20200206144 Lauren Lukas VanderSpek 2020 [191]

Therapeutic cationic peptides and

unimolecular nanoparticles for

efficient delivery thereof

US20200276130 Wisconsin Alumni Research

Foundation

2020 [192]

6. Clinical Trials of Nanotechnology-Based Formulation for Breast Cancer Therapeutics

The outlook of the nano-medicine industry for cancer therapy is quite optimistic. It is

well known and scientifically illustrated that such formulations tend to augment anticancer

medicines drugs' efficacy to facilitate specific selective drug delivery. Table 3 outlines clinical

trials involving the study of nano-formulations for the treatment of breast cancer.

Table 3. Recent clinical trials conducted for breast cancer therapeutics.

Study Title Sponsor NCT No. Phase Refs.

A clinical trial to study the effects of

nanoparticles-based paclitaxel drug, which

does not contain the solvent cremophor, in

advanced breast cancer

Fresenius Kabi

Oncology Ltd.

NCT00915369 Phase 1 [193]

Bevacizumab, doxorubicin, and

cyclophosphamide followed by paclitaxel

albumin-stabilized nanoparticles

formulation and bevacizumab in treating

patients who have undergone surgery for

early-stage breast cancer

Memorial Sloan

Kettering Cancer

Center

NCT00436709 NA [194]

Paclitaxel albumin-stabilized nanoparticles

formulation in treating patients of different

ages with metastatic breast cancer

City of Hope Medical

Center

NCT00609791 Phase 2 [195]

Targeted biopsy of carbon nanoparticles

labeled axillary node for cn+ breast cancer

The First Affiliated

Hospital with Nanjing

Medical University

NCT04482803 NA [196]

Nanoparticles Albumin-Bound (Nab)

Paclitaxel/Cyclophosphamide in Early-Stage

Breast Cancer

SCRI Development

Innovations, LLC

NCT00629499 Phase 2 [197]

Topical Fluorescent Nanoparticles

Conjugated Somatostatin Analog for

Suppression and Bioimaging Breast Cancer

Al-Azhar University NCT04138342 Phase 1 [198]

An early-phase study of abraxane combined

with phenelzine sulfate in patients with

metastatic or advanced breast cancer (epi-

primed)

EpiAxis Therapeutics NCT03505528 Phase 1 [199]

Carboplatin and nab-paclitaxel with or

without vorinostat in treating women with

newly diagnosed operable breast cancer

Sidney Kimmel

Comprehensive Cancer

Center at Johns

Hopkins

NCT00616967 Phase 2 [200]

Doxorubicin hydrochloride,

cyclophosphamide, and filgrastim followed

by paclitaxel albumin-stabilized

nanoparticles formulation with or without

trastuzumab in treating patients with breast

cancer previously treated with surgery

University of

Washington

NCT00407888 Phase 2 [201]

Nab-paclitaxel and bevacizumab followed

by bevacizumab and erlotinib in metastatic

breast cancer

University of

Washington

NCT00733408 Phase 2 [202]





Study Title Sponsor NCT No. Phase Refs.

A study to evaluate safety/tolerability of

immunotherapy combinations in participants

with triple-negative breast cancer or

gynecologic malignancies

Arcus Biosciences, Inc. NCT03719326 Phase 1 [203]

Carboplatin+Nab-paclitaxel, Plus

Trastuzumab (HER2+) or Bevacizumab

(HER2-) in the Neoadjuvant Setting

University of

California, Irvine

NCT00618657 Phase 2 [204]

Targeted silica nanoparticles for real-time

image-guided intraoperative mapping of

nodal metastases

Memorial Sloan

Kettering Cancer

Center

NCT02106598 Phase 1 Phase 2 [205]

Schedules of nab-paclitaxel in metastatic

breast cancer (snap)

International Breast

Cancer Study Group

NCT01746225 Phase 2 [206]

Phase II lapatinib plus nab-paclitaxel as first

and second-line therapy in her2+ mbc

Novartis

Pharmaceuticals

NCT00709761 Phase 2 [207]

Neoadjuvant pembrolizumab(pbr)/nab-

paclitaxel followed by

pbr/epirubicin/cyclophosphamide in tnbc

(nib)

Institut fuer

Frauengesundheit

NCT03289819 Phase 2 [208]

Nanoparticles albumin-bound rapamycin in

treating patients with advanced cancer with

mtor mutations

Mayo Clinic NCT02646319 Early Phase 1 [209]

Nab-paclitaxel and alpelisib for the treatment

of anthracycline refractory triple-negative

breast cancer with pik3ca or pten alterations

M.D. Anderson Cancer

Center

NCT04216472 Phase 2 [210]

Cryoablation, atezolizumab/nab-paclitaxel

for locally advanced or metastatic triple-

negative breast cancer

Mayo Clinic NCT04249167 Early Phase 1 [211]

Nab-paclitaxel and durvalumab with or

without neoantigen vaccine in treating

patients with metastatic triple-negative

breast cancer

National Cancer

Institute (NCI)

NCT03606967 Phase 2 [212]

Study to evaluate cort125134 in combination

with nab-paclitaxel in patients with solid

tumors

Corcept Therapeutics NCT02762981 Phase 1 Phase 2 [213]

7. Conclusions

Conventional chemotherapy approaches have numerous drawbacks like lack of

selective toxicity, damage to normal tissues, poor bio-distribution and drug penetration, and

the tendency of greater drug deposition in normal viscera. Polymeric nanoparticles have

various advantages, including passive or active drug targeting in tumor tissues and improved

intracellular penetration. Several publications, patents, and clinical trials based on the

application of polymeric nanoparticles for breast cancer treatment give the impression that the

integration of polymeric nanoparticle-based techniques in cancer therapy will be an innovative

and futuristic approach producing superior efficacious and drug targeting with reduced toxicity.

8. Current & Future Developments

The integration of current nanoparticles based techniques will be part of the future of

anticancer therapy. Consequently, it’s essential to decide which approaches perform effectively

in a coordinated way to acquire the maximum anticancer effect. The optimal pharmacological

treatments to kill cancer cells can be developed by comprehending the underlying mechanisms

under which medicines destroy tumor cells. Nowadays, the most effective chemotherapeutic

approach is nanoparticle-based medicines. Undoubtedly, to maximize traditional

chemotherapy's therapeutic effectiveness, the domain of nano-medicine can be explored in

prospects.





Funding

This research received no external funding.

Acknowledgments

The authors express gratitude to Chitkara College of Pharmacy, Chitkara University, Punjab,

India, for motivational support for this review's compilation.

Conflicts of Interest

The authors declare no conflict of interest.

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